P1268: DELINEATING THE NEOANTIGEN BURDEN AND TUMOUR MICROENVIRONMENT IN PATIENTS WITH DIFFUSE LARGE B CELL LYMPHOMA (DLBCL).
Authors: Y. Jiang, D. Jin, C. Henneges, E. Penuel, H. J. Hiew, J. N. Paulson, A. Bazeos
Journal: HemaSphere (2022)

Background: DLBCL is a heterogeneous neoplasm classified into 2 main cell-of-origin (COO) subtypes; activated B cell (ABC) and germinal centre B cell (GCB), with ABC having a worse clinical prognosis. Neoantigens are highly selective and immunogenic tumour antigens which result from somatic hypermutations in malignant cells. Aims: The neoantigen landscape in DLBCL has been relatively underexplored. Therefore the aim of this study was to characterise the neoantigen burden (NAB) in DLBCL by COO subtype as well as elucidate the relationship between NAB, tumour microenvironment and disease pathogenesis. Methods: Data were obtained from patients enrolled with previously untreated DLBCL in the Phase III GOYA study (NCT01287741). COO was determined by standard gene expression profiling. Neoantigens were identified and analysed using the Roche/Foundation Medicine neoantigen pipeline where NAB is defined as the total number of predicted neoantigens per patient. The immunedeconv R package was used to analyse the immune cell fractions from bulk RNA-seq data. Post-hoc, exploratory data analysis was performed in R. Results: A total of 404 patients with both COO and NAB data recorded were available for analysis; 272 GCB (67%) and 132 ABC (33%). Overall, the median NAB was 2 with no significant difference between the two COO subgroups (Kruskal wallis chi-squared 0.63, p= 0.42). Next, 449 patients with COO and immune cell fractions data were assessed. A greater proportion of M1 macrophages were present in patients with GCB compared to ABC COO subtype (Kruskal Wallis chi-squared 7.66, p value <0.01). Conversely, higher fraction of M2 macrophages were identified in the ABC compared to GCB subtype (Kuskal Wallis chi-squared 31.39, p <0.001). Of note, there were no significant COO differences in the proportions of CD4+ T cells, CD8+ T cells or T regulatory cells. Of the 444 patients with NAB and immune cell fraction data available. There was a negative correlation between NAB and CD8+ T cell (Pearson correlation -0.162, 95% CI (-0.25, -0.07), adjusted p <0.01; Spearman correlation -0.134, 95% CI (-0.22, -0.04), adjusted p = 0.05). No statistically significant correlation with other immune cell subsets, including macrophages, CD4+ T or T regulatory cells were identified. Summary/Conclusion: To our knowledge this is the first study exploring the complex interplay between neoantigen formation and the tumour microenvironment in DLBCL patients. We report that a greater neoantigen burden is correlated with lower CD8+ T cell fraction; this could represent a potential tumour evasion mechanism. In addition, we find that whilst there is no difference in neoantigen burden between cell of origin subtypes, a significant variation exists in the tumour microenvironment composition, particularly with respect to M1 and M2 macrophage proportions. Further studies are needed to understand the prognostic impact and clinical significance of these findings.